Sensor controlled analysis and therapeutic delivery system

ABSTRACT

A method and apparatus for non-invasively withdrawing and accurately evaluating analytes quickly, painlessly and reliably from a biological subject automatically and controlling subsequent administration of therapeutic agents in response to such analyte sample analysis. Improvements are provided in electro-osmotic sample withdrawal, dosimetry and iontophoretic delivery subsystems, biosensors electrode construction and arrangement, intervenors, mediators, bolus delivery, and related subsystems.

RELATED APPLICATIONS

[0001] This application is a divisional of Ser. No. 09/522,522 filedMar. 10, 2000 which is a divisional application of Ser. No. 09/028,832filed Feb. 24, 1998 now U.S. Pat. No. 6,059,736 issued May 9, 2000.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates generally to a new and improved system forsampling and analysis of body fluids and the like, and may also includedelivery of therapeutic agents in response to such analysis. Moreparticularly, the invention relates to new and improved methods andapparatus for non-invasively withdrawing analytes from a biologicalsubject automatically and controlling subsequent administration oftherapeutic agents.

[0004] 2. Description of the Related Art

[0005] Diagnosis for many human ills is dependent on evaluation ofinvasive samples of body fluids taken for assay. This invasive procedureis accomplished by withdrawal of the analyte or sample through a needleor the like, with consequent exposure of the patient to injury, possibleinfection and discomfort. The procedure invariably involves medicalprofessionals that add to the cost of the procedure, e.g. an officevisit.

[0006] Advances have recently been made in the biosensor field thatenable diabetics, for instance, to self-test through the convenience ofkits such as the ExacTech® device disclosed in U.S. Pat. Nos. 4,545,382& 4,711,245. Such a device, while performing a valuable service andrepresenting a quantum leap over professional intervention, is however,still invasive and subjects the patient to the same risks throughmultiple pin pricks and the like.

[0007] One approach to overcoming the aforementioned major shortcomingsof invasive procedures is by noninvasive electro-osmotic analytewithdrawal through the unbroken skin or mucosal membrane.Electro-osmosis, sometimes referred to as cataphoresis and/or reverseiontophoresis, was recognized before 1941 by Nernst who showed that ureaand sugar can be electrically transported out of the unbroken skin. Anextensive bibliography exists on this basic phenomena.

[0008] A recent effort by Guy, et al., e.g. as described in U.S. Pat.Nos. 5,279,543 and 5,362,307, attempts to use this basic electro-osmosistechnology to extract glucose. However, these attempts fall short ofpractical success because the proposed technology cannot perform thedesired withdrawal procedure within a time span of less than tenminutes, as medically needed so that a glucose measurement would befollowed in a timely manner after determination of the appropriatetherapeutic insulin level. In this regard, continuously rapid changes ofglucose levels, which commonly occurs, require different therapeuticinsulin levels. Such limiting constraints on faster performance ofsample withdrawal by the prior art is due to the restricted levels ofcurrent, voltage and time duration for the device to extract a sampleand yet prevent skin injury. Accordingly, the prior art systems offernothing new in basic electro-osmosis technology to prevent skin injury.Moreover, there is no subsequent controlled automatic delivery of anappropriate therapeutic agent in response to such rapid samplewithdrawal and analysis.

[0009] Further difficulties have been encountered in achievingsatisfactory dosimetry control for iontophoretic administration systems.

[0010] Hence, those concerned with the development and use of analytewithdrawal and evaluation systems have long recognized the need for veryrapid, painless, accurate, non-invasive analyte withdrawal and analysisand subsequent controlled automatic delivery of therapeutic agents inresponse to such analysis. The present invention clearly fulfills allthese needs.

SUMMARY OF THE INVENTION

[0011] Briefly, and in general terms, the present invention provides anew and improved system for sampling and analysis of body fluids, e.g.,analytes, and delivery of therapeutic agents in response to suchanalysis and, more particularly, to improvements in methods andapparatus for non-invasively withdrawing and accurately evaluatinganalytes quickly, painlessly and reliably from a biological subjectautomatically and controlling subsequent administration of therapeuticagents in response to such analyte sample analysis.

[0012] By way of example, and not necessarily by way of limitation, thepresent invention provides a system wherein limits of low electricalvoltage and current previously imposed on prior art systems to preventskin injury, are now overcome through unique electrical circuitry andlong tunnel physical routing of applied electrical voltage, therebyachieving high sampling current density. This facilitates rapid samplingwhich can be completed well under 10 minutes. In this regard, theprocess of the present invention enables use of 60 volts or moreproducing a controlled sampling current for complete comfort, andprovides an analyte reading in 15 seconds or less.

[0013] In accordance with the invention, the aforedescribed features areaccomplished, in part, by providing a long tortuous path between theapplied high voltage and the skin of a biological subject. This pathbetween the voltage source and the skin typically consists of a solventor water wetted wool as an intervenor. Since the injury is caused bysodium hydroxide (lye) migrating from the negative voltage sourceelectrode, the wool (or composite) acts as a barrier to the rather largesodium hydroxide molecule to prevent injury within the 10 minutetreatment period.

[0014] Since one aspect of the invention involves a diagnostic tool,accuracy and repeatability are paramount. To achieve this, the inventionprovides that the current and time used to obtain the analyte sample beintegrated and interdependent on each other, so that the identicalquantitative sampling is always obtained. In this way, the identicalamount of analyte is always withdrawn as a sample, despite thesubstantial variabilities of skin resistance on an individual.

[0015] Another aspect that limits the use of higher electrical currentsis the pain involved. Usually, both electrical polarities are in directcontact with the skin through a felt or gel intervenor. Of the twopolarities, the sensation at the positive electrode is typically farmore painful. If therefore, direct contact of the positive electrode isremoved from the skin, it allows a large increase in sampling currentwithout the discomfort normally associated with such electrical currentsand while still obtaining the analyte such as glucose at the negativeelectrode.

[0016] To eliminate pain caused by the positive polarity at highcurrents, additional novel technology is provided in accordance with theinvention. Previously used circuitry in iontophoresis used bothelectrical polarities applied to the skin surface to “complete” orground the circuit. In the practice of the present invention, thenegative polarity is chosen to sample an analyte such as glucose and thepositive electrode is no longer directly connected to the body as aground return but stays within the device housing with its droppingresistor connected to the skin (ground) to complete the circuit. Thisground is essentially neutral electrically. The negative polarity is inelectrical contact with the skin through the aforedescribed wetted, longwool inter-venor and then through a wetted membrane on the skin whichacts as a collector for the analyte. Of course, for other applicationsthese polarities could be reversed and, again, only a single electricalpolarity is in contact with the skin.

[0017] The present invention also provides a system to assay or measurethe sample. A pair of electrodes are provided facing each other withanalyte selective enzyme coated on one electrode, e.g., the workingelectrode, or, alternatively, on the membrane facing the workingelectrode. A bi-layer membrane is inserted between these electrodes andserves the purpose of connecting directly to the skin on one end whilethe other end is in contact with the long narrow intervenor that isconnected to the high voltage negative source. When wetted with anelectrolyte of pH 7.4, a continuous circuit is provided from this highvoltage source to the skin (with felt pad and membrane in between).Thus, in accordance with the invention, a “sandwiched” bi-layer membranein between an enzyme coated electrode(s) or membrane is provided as amechanical structure to extract the analyte sample and convey it to anyappropriate digital readout subsystem.

[0018] The biosensor circuit is separate from the withdrawal circuit andcomes into play after the analyte sample has been withdrawn. Thedosimetry circuit turns the device on for the predetermined setting ofless than 15 ma./sec., for example, to extract the analyte. Uponcompletion of this cycle, the readout subsystem is activated andprovides a reading on its digital display. Of course, any number ofdetection systems are available and would be suitable for the readoutsubsystem, including those in the public domain.

[0019] In accordance with the invention, electronically produced gasesserving as a mediator are generated at the high voltage negativeterminal. The negative polarity, besides producing the necessary currentto withdraw the analyte, also produces hydrogen gas at the negative polewhich migrates towards the positive pole and thus passes through themembrane and between the biosensor electrodes. The hydrogen gas is areduction agent and reduction cannot exist without oxidation. Thisoxidizes the immobilized enzymes on the electrodes/membrane and thecaptured glucose analyte. This also causes electron transfer to theelectrodes that is proportionate to the concentration of analyte.

[0020] Hydrogen gas is an excellent redox species and is far superior tothe “one shot” mediator of prior art devices, such as that utilized inthe well-known and commercially available ExacTech® system, because itcomes from a renewable source. This process also produces the halogenchlorine which further aids in oxidation.

[0021] In addition, in accordance with the invention, the high voltagesource is dosimetry controlled and, therefore, not only quantitativelycontrols the analyte withdrawal, but also controls the quantity of theaforementioned hydrogen/chlorine gas mediator which is generated.

[0022] This negative electrode generated hydrogen also serves otherimportant functions. Since hydrogen has a special affinity for palladiumand will permeate its surface, this may be used to advantage byproviding a sensor electrode of palladium. Hydrogen interacts with thepalladium to lower resistance. If the working electrode is palladium andthe second electrode is of the hydrogen resistive alloy NASA-23 or itsequivalent, the resistance or work function between both electrodes islowered. Because the NASA-23 or equivalent electrode is impervious tothe hydrogen gas, it serves as an excellent reference electrode relativeto the palladium electrode.

[0023] Still other benefits accrue when hydrogen ions combine with thesolvent water molecules to create hydronium ions. The hydronium ions arecrucial to the cellular processes which lead to enzyme catalysis andmembrane transport.

[0024] In accordance with the invention, very high potentials (over 1v.) are provided to cause the redox reaction. There is a two-stepprocess, i.e., 1) a high voltage to cause the redox (generated by thereducing agent hydrogen), and 2) then revert to an extremely smallvoltage (under 1 v.) to activate the transducer and readout system. Thisoccurs almost instantaneously because the conventional time of 20-30seconds to await the redox reaction has already taken place in much lesstime by the high voltage caused hydrogen that led to that event inshorter time than any prior art device.

[0025] Accordingly, and in view of the foregoing, the process of thepresent invention includes application of a large negative voltage to asmall area of the skin to cause the electro-osmotic withdrawal of bodyfluids. This same high voltage has another attribute in that itgenerates hydrogen—the same hydrogen gas that will lead to the oxidationof the glucose enzyme(s) that separates out the glucose analyte frominterferents. This causes the cycle of events that will result inelectron transfer from the closely associated enzyme(s) coatedelectrodes or membranes to provide a measure of glucose concentration.Moreover, the source for the hydrogen is unlimited and repeatable,therefore making the process available on demand without the physicalpresence of any consumable chemical mediators. Since the enzymes arereusable, the economy and simplicity of operation of such a deviceprovides clear advantages to the patient.

[0026] To reuse the device and obtain new glucose measurements andrepeat the events leading to insulin infusion, known as recovery time,the second half of the one cycle long signal may (optionally) reversepolarity and return the system to neutral. Alternatively, one just hasto wait several minutes for the hydrogen to dissipate, and the entireprocess can then be repeated.

[0027] Another feature of the present invention that improves the minutesampling taken through the unbroken skin is the use of the amplificationor regeneration capability of certain chemical combinations. If theelectrodes are coated with coupled enzymes, such as glucose oxidase orglucose dehydrogenase in the presence of cofactors NAD/NADH and HADPH orNADH, then the extremely minute analyte coming through the skin is “pingponged” between competitive enzymes and, therefore, multiplied. Anotherbenefit of this is improved separation between the target glucose andinterferents.

[0028] Hence, various aspects of the present invention facilitatenoninvasively withdrawing body fluid and provide novel sensor technologyto create a mediator and to control the quantity of this mediator foraccurately determining analyte concentration for diagnostic purposes.These inventive features can be used separately or in combination andthey both use common components that have multiple functions. This dualcapability of noninvasive sampling and controlling the target inorganicor organic substance is a linchpin to the control and operation of atherapeutic drug delivery unit such as that described in U.S. Pat. No.5,224,927 by the same inventor, Robert Tapper, as the present invention.This “closed loop” arrangement provides for self-regulated insulininfusion controlled by the monitored glucose reading using the biosensordescribed above. The entire device can fit into an externally worn,topically applied “patch”.

[0029] Another important feature referred to in U.S. Pat. No. 5,224,927is the ability of this device to adjust the pH of the drug deliveryreservoirs and/or a biosensor skin contact membrane (known as BLM ors-BLM). The pH adjustment range is approximately 4 to 8 and can aid inpermeability for both infusion of drug or increasing withdrawal ofanalyte. For instance, in view of the nonconductive wetted collectionbi-layer membrane (BLM) in contact with the skin, and in view of thepoorly conductive insulin in the drug delivery chambers, optimalperformance would take place if the solution were adjusted to theappropriate pH. An important function of the s-BLM membrane is that itcan be used as a pH probe for pH measurement. The resulting pH data isthen the basis for any suitable pH control circuit to adjust pH asneeded.

[0030] The aforedescribed system of the present invention relates inparticular, and only by way of example, to the needs of a diabetic.Another need of the diabetic is that they be given a “bolus” shot ofinsulin at mealtime. A bolus shot requires the infusion of a large doseof insulin compared to the patient's baseline maintenance level ofinsulin. The system described in U.S. Pat. No. 5,224,927 is readilyadapted to meet this demand for an extra large dose in the followingmanner.

[0031] By activating a designated electrical bolus switch, both drugdelivery reservoirs of the patch are made active simultaneously insteadof their normal operating mode of sequential drug delivery (due to thevery slow A.C. operating signal). Since the bolus switch causes bothreservoirs to deliver insulin simultaneously by giving them theidentical negative polarity, the dosage is thereby doubled overbaseline.

[0032] As previously indicated, the positive polarity stays within theelectronic patch housing and is connected to the skin through a droppingresistor. The skin or ground is relatively neutral at this point. Thisfeature lifts the positive polarity off the skin, thereby eliminatingthe more painful and non-contributing polarity from skin contact. This,in turn, allows the patient to at least double the electrical currentsetting, thereby again doubling dosage for a total of four times overmaintenance level for short term delivery. For this short term deliverya D.C. signal is used. Because it is a D.C. signal, skin injury could beexpected unless corrective action were taken. Until now, the use of thepH control circuit served the singular purpose of optimizingpermeability and, therefore, delivery by making the solvent compatiblewith the drug of choice and its polarity.

[0033] In accordance with the invention, pH control is also used toprevent skin injury when using D.C. for the short term. For instance, inthe example cited above, the negative polarity was used to drive insulinfrom both reservoirs. The injurious sodium hydroxide generated at thenegative pole must then be offset. This can be done by pretreating withthe positive polarity, thereby building an acidic reserve pH ofapproximately 4 (by way of example) in the drug delivery reservoirs.Drug delivery is then activated with a negative polarity driving thepretreatment pH up toward the alkaline state. Before the reservoirsreach pH 8, the delivery signal must be stopped for another short dosageof pH 4 caused by the positive polarity. Thus, in the practice of thepresent invention, injury is prevented by avoiding extremes of pH asmeasured by the s-BLM probe.

[0034] The present invention also includes a unique electrode systemthat allows current to be elevated at least 200% over present levels. Apair of large drug delivery electrodes is provided. In accordance withthe invention, another pair of ancillary electrodes are added on theoutside perimeter of the drug delivery electrodes. These ancillaryelectrodes also cross between and are insulated from the drug deliveryelectrodes. The outer ancillary electrodes are also typically driven ata frequency of approximately one cycle per minute. This is the secondharmonic of the basic drug delivery generator whose frequency isapproximately one cycle every two minutes. It has also been discoveredthat the use of sodium salicylate instead of tap water with theseancillary electrodes is able to further mask the pain sensation arisingfrom the drug delivery electrodes, so as to facilitate additional largeincreases in the drug delivery electrical current levels.

[0035] Another important need for a bolus shot is in the field ofanesthesia since it is desirable for quick action to alleviate pain. Thesame procedure for elevated infusion applies as described above with pHcontrol to avoid injury, but may require switching polarities since manyanalgesics are positive. In this regard, and by way of example, a D.C.signal is used with novel circuitry to obtain greatly elevated drugdelivery levels without skin injury or pain. To lessen pain and skininjury from the positive reservoirs, these electrodes are connectedthrough a dropping resistor, instead of connecting them directly to thepositive terminal of the voltage supply. This causes a large drop acrossthe resistor and makes the electrode relatively less positive than thesource voltage. Electrical current still flows because the negativepolarity is directly connected to the skin through the wetted pad. Thisprovides a lifting and isolation of the pain-causing high positivevoltage relative to the skin, and also allows increased electricalcurrent and therefore faster therapy. Diminished positive voltage at theskin also decreases the potential for irritation from this contact.Importantly, it has been discovered that adding sodium salicylate to thenegative pad also diminishes skin injury which would be a concern with aD.C. device.

[0036] The aforedescribed artificial pancreas of the present inventionhas obvious advantages over present day invasive systems that includeexpensive and risky implants.

[0037] It is to be understood that the noninvasive biosensor describedabove used glucose as the target analyte only as an example and not byway of limitation. For instance, there are hundreds of differentdehydro-genases and several thousand enzymes. Besides glucose analysis,important diagnostic applications could include, again by way of exampleonly, urea, creatinine, lactate, cholesterol, aspirin and paracetamol,among others. In addition, noninvasive sample analysis may be made ofbody fluids to compare then to normal levels or to track administereddrug levels.

[0038] Since the present invention focuses on a means of determining theconcentration of chemical or body fluid components to assess acondition, another important application is facilitated. Duringiontophoretic drug delivery, it has long been an enigma to determinewhat portion of the reservoir drug has been infused. In this regard, thesame means of determining concentration with the biosensor describedabove may be applied to assessing the drug remnant in a drug infusingdevice, therefore assuring the user of adequate drug availability, etc.This occurs because a decrease of concentration indicates percutaneousabsorption into the body of the solute or drug. This information mayalso be important to the investigator during the testing of a new drug,for quantitative analysis of drug related to an effect. The presentinvention thus nominally replicates the extremely expensive HPLC labinstrument at a fraction of the cost.

[0039] Still another important application in accordance with theinvention, comes about as a result of this ability to assess drugconcentration in an iontophoretic drug delivery reservoir. It has alwaysbeen a problem to have an adequate supply of drug available in the drugreservoir for long term, continuous delivery. It is not practical tomake an overly large patch because it must be worn and would meetpatient objection. Moreover, the literature places concentrationrestrictions on iontophoretic drug delivery to 2% solutions, claimingreduced flow above this point because of ionic clutter. In accordancewith the present invention, a novel way of eliminating this problem andallowing delivery over time with a relatively small patch is to providea reserve reservoir that contains a concentrate of the desired drug inaqueous solution. This concentrate is considerably over 2% —perhaps 20or 50%. Upon receiving information from the drug delivery reservoir thatthe concentration is less than the initial filling of 2%, the biosensortriggers the reserve reservoir to release enough of the concentrate tomake up the difference that was infused. In this manner, the drugdelivery reservoir is continuously replenished.

[0040] The structure of the reserve reservoir is a separate compartmentfor the concentrate with a membrane covered opening. The membrane has avoltage across it with selective polarities to act as a valve to open orshut off the flow of concentrate as needed. This action may be enhancedwith an ion exchange membrane. The solvent is replenished automaticallyby virtue of the fact that an A.C. signal is used. This causes thehydrogen and hydroxide ions to migrate together to form water.

[0041] Various other embellishments known in the art can be practiced inthis invention. They include immobilization of the enzyme biocomponentand restriction of the flow of analyte diffusion. The best biosensordesign is to build a “direct” device with biocomponents immobilizeddirectly on the transducer. Other characteristics of constructioninclude the close proximity of the biological and physicochemicalcomponents to each other to improve efficiency.

[0042] The present invention also provides in combination with theaforedescribed sample withdrawal and assay, and in response toelectrical input from the assay subsystem, a new and improved method andapparatus for applying electrical energy topically to a suitable surfaceof a biological subject, such as the skin of a human body, particularlyfor the long term administration of medicaments and the like or forother electrotherapeutic treatment, and by which the aforementioneddeficiencies and undesired side effects are greatly minimized and may beeliminated.

[0043] Moreover, the system of the present invention is relativelyinexpensive to manufacture, can be physically packaged in a completelyself-contained, relatively simple and compact configuration, is troublefree and reliable in use, is capable of higher drug administration ratesand drug concentrations, can deliver multiple drugs simultaneously in asimple manner, can control pH at the delivery site, is capable ofdelivering large and/or heavy molecule drugs, is a more effectivebactericidal, and is arranged to be safely, simply and reliably operatedfor self-treatment by an average person in normal home use, even forextended periods of several days at a time to unlimited use for thechronically ill patient. Furthermore, it is contemplated in the practiceof the invention that electrical impedance at the administration site onthe patient can be substantially reduced to vastly improve permeabilityand penetration and thereby further enhance medicament delivery.

[0044] In this regard, the present invention is directed to thecombination of a new and improved system for iontophoretic drugadministration, in response to an assay measurement signal, whichincludes conducting direct electrical current through the skin of abody, and periodically reversing the electrical current and conductingthe current through the skin in the opposite direction, to effectivelydeliver very low frequency A.C. current, substantially in the criticalrange of approximately 0.0027 Hz to 10 Hz. It has been discovered (seeU.S. Pat. No. 5,224,927) that, within this substantially criticalfrequency window between approximately six minutes per full cycle andapproximately ten cycles per second, a dramatic cancellation of skindamaging ions takes place. At frequencies higher than approximately 10Hz, no substantial effective delivery takes place. At frequencies lowerthan approximately 0.0027 Hz, the risk of skin injury increasessubstantially.

[0045] As previously indicated, it is well known that the positiveiontophoretic electrode, in addition to its primary function of drivinglike polarity ionic substances into the skin of a subject, unfortunatelyproduces skin damaging hydrochloric acid as well. Likewise, the negativeiontophoretic electrode, in addition to its primary function of drivinglike polarity ionic substances into the skin, unfortunately alsoproduces skin damaging sodium hydroxide. However, within the aforestatedfrequency range of the present invention, either driving polaritydelivers the desired ionic therapeutic substances, but also cancels theundesired skin damaging ions with the reverse portion of the electricalcycle. The reason for neutralization of the harsh injury producingchemicals, i.e., hydrochloric acid and sodium hydroxide, is that both ofthese chemicals require a finite period of time on the skin to causedamage. Hence, these damaging chemicals are made to cancel each otherbefore damage takes place, by critical frequency selection, inaccordance with the invention, of the A.C. driving signal. Therefore,optimization of a long sought therapeutic device with reduced sideeffects has been achieved.

[0046] In this regard, electronic circuitry is provided to automaticallyimpose the reversal of electrical current at regularly repeatingintervals of time, in accordance with the aforedescribed substantiallycritical frequency range, and the system can be adjusted to conduct theiontophoretic treatment at any desired level of electrical current, suchtreatment being under the control of the previously described samplewithdrawal and assay subsystem.

[0047] The present invention also provides, as previously indicated, amethod and apparatus for electrical dosimetry control in the applicationof electric currents to withdrawal of analyte samples, dosimetry insample withdrawal being determined automatically by the product of timeand administered electrical current. In this regard, the presentinvention is directed to a system for electrical dosimetry measurementand control, wherein the product of administered electrical current andtime for total dosage is maintained constant, while either variable,time or electrical current magnitude, may be changing.

[0048] By way of example and not necessarily by way of limitation, thesystem includes means for automatically establishing the magnitude ofthe desired total sample withdrawal dosage in terms of deliveredtime-current product and means for sensing the magnitude of theelectrical current and converting that magnitude to a voltage forvarying the frequency of a voltage controlled oscillator as a functionof the electrical current magnitude. Means are also provided formeasuring and accumulating the electrical output of the oscillator overtime, in a suitable counting device, as an indication of the actuallydelivered time-current product. In addition, means are provided forcomparing the delivered time-current product registered in the counter,as a running measure of withdrawn sample dosimetry during the samplingprocedure, with the desired total dosage previously established, so thatthe application of the sample withdrawing electrical current will beterminated when the time-current product actually administered equalsthe desired total withdrawal dosage.

[0049] The new and improved electrical dosimetry control system of thepresent invention for sample withdrawal is extremely accurate, reliableand easy to use. The system provides enhanced patient comfort and highprecision in automatically establishing administered electrical currentdosage for consistent sample withdrawal.

[0050] Hence, the present invention provides a new and improved methodand apparatus for very rapid, painless accurate, non-invasive analytewithdrawal and analysis and subsequent controlled automatic delivery oftherapeutic agents in response to such analysis. The invention alsoprovides new and improved subsystems and components for enhancing thepractice of the invention.

[0051] These and other objects and advantages of the invention willbecome apparent from the following more detailed description, when takenin conjunction with the accompanying drawings of illustrativeembodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0052]FIG. 1 illustrates an iontophoretic patch sample withdrawal,evaluation and administration device constructed in accordance with theinvention, and shown installed upon the arm of a human subject;

[0053]FIG. 2 is an enlarged, perspective view of a presently preferredembodiment of a patch constructed in accordance with the invention,portions being broken away to illustrate internal structure;

[0054]FIG. 3A is a sectional view, taken substantially along the line3A-3A in FIG. 2;

[0055]FIG. 3B is a sectional view, taken substantially along the line3B-3B in FIG. 2;

[0056]FIG. 4 is an exploded perspective view of a biosensor and fluiddelivery device, constructed in accordance with the present invention;

[0057]FIG. 5 is a block diagram of an electrical system for non-invasiveanalyte withdrawal, evaluation and therapeutic agent delivery inaccordance with the present invention;

[0058]FIG. 6 is a combined electrical diagram and perspective viewillustrating a portion of a biosensor and fluid delivery device, inaccordance with the present invention;

[0059]FIG. 7a-7 d are enlarged perspective views of biosensor electrodesand membrane construction, in accordance with the invention;

[0060]FIG. 8 is an enlarged, perspective view of another biosensorelectrode construction, in accordance with the invention, and havingmultiple diagnostic capabilities; and

[0061]FIG. 9 is a cross-sectional view of another embodiment of theinvention, illustrating new and improved electrode construction.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] Referring now to the drawings, like reference numerals denotelike or corresponding parts throughout the drawing figures.

[0063] As best observed in FIG. 1, there is shown a combinedelectro-osmotic analyte withdrawal, evaluation and iontophoretic patchadministration device 10, of relatively simple, economical, reliable andcompact construction, embodying features of the present invention. Thepatch 10 is shown installed upon the arm of a suitable biologicalsubject so that the patch contacts the skin 11 of the subject forappropriate analyte withdrawal, assay and subsequent administration oftherapeutic treatment by iontophoretic delivery of medicaments or thelike. By way of example, the patch 10 is held in position by a pair oftapes 19.

[0064] While the device 10 is shown in its presently preferredembodiment as a compact patch, it will be appreciated by those ofordinary skill in the art that a larger structural and/or physicalpackaging unit (not shown) may be utilized and also embody variousfeatures of the present invention.

[0065] The structural details of the portion of the patch 10 and theadministration system relating to iontophoretic treatment are set forthin U.S. Pat. No. 5,224,927, issued Jun. 6, 1993, inventor Robert Tapper,the same inventor as the present invention, and all of the disclosure ofthat patent is specifically incorporated by reference in thisspecification as if set out completely herein.

[0066] As best observed in FIGS. 2, 3A and 3B of the drawings, theiontophoretic patch 10 is a very compact, circular, cylindrical devicefabricated primarily of an outer plastic shell with internal, preferablyintegrally molded, baffles. The plastic shell and baffles are typicallymolded of an electrically insulating, flexible vinyl material or thelike.

[0067] The internal baffles divide the interior of the iontophoreticpatch 10 into upper and lower, hollow internal chambers 12 and 13,respectively, more specifically, by means of an interior baffle member14. The upper chamber 12 contains a compact electronics package 15,including a suitable microchip and battery power supply. This upperchamber 12 is electrically insulated from the lower chamber 13 by theplastic baffle member 14.

[0068] The lower chamber 13 contains a pair of iontophoretic electrodes,16 a and 16 b, typically of electrically conductive silicone/carbonmaterial, and which are separated from each other by a pair ofelectrically non-conductive plastic divider baffles 17 forming separatorwalls which divides the lower compartment 13 into a pair ofsemi-circular electrode chambers and reservoirs 18 a and 18 b and anarrow chamber for an electrode to be described subsequently herein. Thechambers 18 a and 18 b house the electrodes 16 a, 16 b and contain thetherapeutic substances to be ultimately infused into the biologicalsubject, the drug infusion path being indicated generally by the arrows20 in FIG. 3B.

[0069] The iontophoretic delivery electrodes 16 a, 16 b are suitablyconnected electrically into the electronics package 15 via electricallyconductive tabs 21 a and 21 b, respectively, extending throughappropriate slotted openings in the chamber dividing baffle member 14.The silicone/carbon electrodes 16 a, 16 b are typically fabricated of1-2 ohm per square centimeter conductive plastic material. While theelectrodes 16 a, 16 b are preferably of silicone/carbon in a presentlypreferred embodiment of the invention, they may be fabricated of otherelectrically conductive, non-corrosive materials as well. With the A.C.delivery signal used in the system of the present invention, there islittle or no resistance build-up in the silicone/carbon electrodes.

[0070] The drug reservoirs 18 a and 18 b are filled either with a gelcontaining the therapeutic substances to be administered or a pair offelt pads 22 a and 22 b which have been appropriately saturated with thesubstances to be dispensed.

[0071] In addition, for manual operation, an electrical slide switch 24,allowing selection of dosage, schedule and treatment duration, projectsphysically, for access by an operator, through an upper plastic coverplate 26 adhered to the top of the outer shell of the iontophoreticdevice 10. The switch 24 is electrically connected in the chamber 12 tothe electronics package 15. The switch 24 may be selectively movedbetween a “0” (off) position, to either a “LO” (low current or lowerrate of drug delivery) or “HI” (high current or higher rate of drugdelivery) switch positions, to either turn the device 10 “off” so as tocease electrical operation, or to set the device for either high or lowelectric current rate operation which can remain in such a state on thepatient, continuously if desired, for typically either 3 days or 7 days,respectively. Battery replacement, as needed, will repeat this serviceinterval.

[0072] The function of the switch 24 in FIG. 1 with markings “0”(meaning off), “LO” and “HI” is as follows:

[0073] 1) The “0” position keeps the device from functioning. It mayalso be used to schedule an “off” interval after leaving one of theother drug delivery positions.

[0074] 2) The “LO” treatment position infuses the drug at the lowestcurrent level at a continuous, controlled rate. This position can beused for drugs with a narrow therapeutic index for low level infusion.Another use for this position could be a drug with a long half-life witha schedule of intermittent “0” positions to avoid an accumulation thatmight otherwise result in toxicity.

[0075] 3) The “HI” treatment position of the switch 24 infuses the drugat a current level typically twice as high as the “LO” setting. Thisposition may be used to maintain efficacy for drugs with a shorthalf-life, such as peptides. Also, the “HI” position can be used for abolus dose coming off the “LO” position, when therapeutically indicated.

[0076] For automatic operation, the manual controls discussed above aresuperceded by the biosensor developed data, to control current level andtime of infusion as determined by the dosimetry system for exactquantitative infusion.

[0077] An LED test indicator 28 extends from the electronics packagechamber 13 below the cover plate 26, through an appropriate opening inthe cover plate, and is observable from the top of the iontophoreticpatch 10 to confirm proper electrical operation of the system for theuser. An additional switch 29, such as a membrane switch located insidethe patch 10 below the cover plate 26, and operable by pressure on theflexible cover plate, (not shown) may be included to selectively connectthe indicator 28 into and out of the electrical circuit, so as tominimize power drain when the indicator is not needed.

[0078] A bolus switch 52 is also provided for initiating and terminatingbolus delivery of medicament in a manner subsequently described areplaceable biosensor 70 includes a pair of juxtaposed electrodes 72 a,72 b with an electrically insulating membrane 74 interposed between thelatter electrodes. An intervenor pad 76 is electrically connected to thebiosensor and to a remote electrical source of high negative D.C.polarity for sample withdrawal of the desired analyte. The intervenorpad 76 provides a long tortuous path between the high negative voltageand the biosensor 70.

[0079] Referring now more particularly to FIGS. 3A, 3B and 4 of thedrawings, the electrodes 16 a, 16 b are located in the drug reservoirs18 a, 18 b (FIGS. 2, 3A and 3B) and are A.C. driven for general drugdelivery, as described in the aforementioned U.S. Pat. No. 5,224,927.For bolus insulin delivery, both electrodes 16 a and 16 b are shortedtogether in parallel and made negative in polarity. Ground return forbolus treatment is provided in peripheral outer thin pads with groundreturn terminals 66.

[0080] The iontophoretic delivery subsystem in the patch 10 is adaptedto be automatically controlled by the dosimetry subsystem in FIG. 5.

[0081] The pH control pads 69 may be made either + or −. The electrode65 is the ground return for pH control.

[0082] The high voltage electrodes 64 provide approximately 60 voltsnegative D.C. to the felt intervenor pad 76 which, in turn, provides along tortuous path for electrical current to the replaceable sensor unit30 which in turn, provided output at terminals 67, 68 in FIG. 5.

[0083] As previously indicated the sensor unit 70 includes a pluralityof sensing and assay electrodes 72 a, 72 b with an appropriate membrane74 therebetween. The structure of the sensor unit 70 is subsequentlydescribed in greater detail with reference to FIGS. 6 and 7 of thedrawings.

[0084] The ground return 63 in FIG. 4 is directed through an appropriateisolation resistor, typically of 5 kilohms, to a remote source ofpositive high voltage (approximately +60 volts D.C.), as shown in FIG.6.

[0085]FIGS. 7a and 7 d show the assembled biosensor 70 with electrodes72 a, 72 b, fabricated of electrically insulating material, and a thinmembrane 74 sandwiched between the electrically conducting electrodesurfaces 68 and 69 located on confronting faces of a pair of electrodesupports.

[0086]FIG. 7b shows the pair of electrodes 72 a, 72 b and supports theirsupports and electrode faces 68, 69 in disassembly to illustrateinternal construction, while FIG. 7c shows the electrodes with themembrane 74, and a reference electrode 80, prior to final assembly toprovide the structures shown in FIGS. 7a and 7 b.

[0087] In a two electrode system as shown in FIG. 7, the electrodes canbe composed of the following materials. For the reference electrode 80(or counter electrode), it is desirable to have an inert but conductivematerial. In view of the fact that negative pole generated hydrogen isused as a reducing agent, it is imperative that the reference electrode80 show maximum stability. A presently preferred choice for thisreference electrode is material NASA-23 available from NASA. Its primecharacteristic is that it is a hydrogen resistant alloy. Othercommercially available choices or equivalents would be materialscommonly identified commercially as A-286, 718, JBK-75 and Incoloy 903.The working electrode 67 would be composed of finely divided palladium(known as palladium black). Hydrogen readily permeates the palladium andin doing so has extended surface which adds to the current.

[0088] Another suitable structure would be for the enzymes to be coatedon the palladium and the palladium to be backed by NASA-23 or itsequivalent. The effect would be for the hydrogen reducing agent todirectly reduce or oxidize the enzymes and for the hydrogen to permeatethe palladium but be reflected back from the NASA-23 or its equivalent.This would maximize the oxidation effect and transfer of electron chargeto the palladium electrode. The bi-layer dielecting membrane 74 (BLM) inbetween the electrodes can actually benefit from a choice of twomaterials i.e., cellulose and Nafion. These membranes may be coated withglucose dehydrogenase and NADH. The two plated electrode surfaces 67, 68facing each other with dielectric membranes 74 in between providecapacitive coupling.

[0089]FIG. 8 illustrates another example of electrode configuration withplural working electrodes 67 a-67 d and corresponding electrical outputs82 a-82 d, respectively, to facilitate multiple diagnostic capabilities.The reference electrode 80 is surrounded by the membrane 74 (not shownin FIG. 8) and is positioned between the working and counter electrodes67, 68.

[0090] Typical dimensions for the various electrodes and the supportmounting structure are also provided in FIG. 8.

[0091] In accordance with the invention, a sensor can be provided whichoperates without enzymes. In this regard, for example, noble metals suchas platinum can be substituted for glucose oxidase to catalyze theoxidation of glucose.

[0092] In the practice of the present invention, the limits of lowvoltage and current imposed on the prior art approaches, such as thosedescribed in U.S. Pat. Nos. 5,279,543 and 5,362,307 to prevent skininjury, are overcome through the aforedescribed unique electricalcircuitry and long tunnel routing of applied voltage through theintervenor 76. In this regard, it is possible to apply 60 to 70 voltsD.C. to the active negative electrode 64 and draw up to 3 milliamps withno injury. This resulted in current density of approximately 6.7 ma. percm2 or approximately 30 times more current than the 0.22 ma. per cm2 ofthe aforedescribed prior art. In addition, the sampling was completedwell within the necessary 10 minutes. Further refinement of the processpermits allowed use of 60 volts producing a controlled sampling currentof 1.5 ma. for complete user comfort, and that provided an analytereading in approximately 15 seconds. The current density for this latermodel was 2.8 ma. per cm2 which was 13 times greater than the currentsproduced in the abovementioned prior art patents. A further experimentalmodel calls for 6.2 ma. per cm2 or approximately 28 times more densitythan described in the aforementioned prior art patents and faster thanthe aforementioned 15 seconds. All of this is accomplished without skininjury.

[0093] Three of the primary features of the invention that make all ofthese desirable advantages feasible are described as follows:

[0094] In accordance with the invention, the aforedescribed features areaccomplished, in part, by providing a long torturous path between theapplied high voltage and the skin of the subject, i.e., via theintervenor 76. This path between the voltage source and the skintypically consists of a solvent or water wetted wool pad; see the pad 76in FIGS. 2, 3A and 4. Since the injury is caused by sodium hydroxide(lye) migrating from the negative voltage source electrode 64, the wool(or composite) acts as a mechanical barrier to the rather large sodiumhydroxide molecule to prevent injury within the maximum 10 minutetreatment period.

[0095] In another embodiment of the invention, an alternative isprovided to a tortuous felt pathway to prevent skin injury by preparinga thin felt intervenor pad (not shown) with a chemical pH that isopposite to the chemical pH of the drug delivery reservoirs 18 a, 18 b.For instance, for the short term analyte withdrawal by the sensor 70, anegative polarity connected to a thin intervenor felt quicklyaccumulates a large quantity of alkaline sodium hydroxide which wouldlead to a burn. However, if the pad is prepped with acidic hydrochloricacid controlled by novel pH circuitry, e.g. or in U.S. Pat. No.5,224,927, this would neutralize any injury causing ions. Anotherapproach is to use a pad that was previously coated with an acid oralkaline chemical to buffer the injurious chemical being generated atthe electrode.

[0096] Since one aspect of the invention involves a diagnostic tool,accuracy and repeatability are paramount. To obtain accuracy andrepeatability, a key requirement in the practice of the invention isthat the current and time used to obtain the analyte sample beintegrated and interdependent on each other so that the identicalquantitative sampling is always obtained; i.e., to obtain consistentanalyte sample size from one measurement to another. In this way, thesubstantial variabilities of skin resistance on an individual andbetween different individuals will always produce the identical amountof analyte which is withdrawn as a sample for subsequent analysis.

[0097] Another aspect that limits the use of higher currents is thepatient pain involved. Usually, both electrical polarities are in directcontact with the skin through a felt or gel intervenor. As previouslyindicated, of the two polarities, the sensation at the positiveelectrode is typically far more painful to the patient. If therefore,direct contact of the positive electrode is removed from the skin, itallows a large increase in sampling current without the discomfortnormally associated with such high electrical current, and still obtainthe analyte, such as glucose, at the negative electrode.

[0098] To eliminate pain caused by the positive polarity at highcurrents, the following novel technology, in accordance with theinvention, is provided. Previously used circuitry in iontophoresis usedboth polarities applied to the skin surface to “complete” or ground thecircuit. In the practice of the present invention, the negative polarityis chosen to sample glucose and the positive electrode is no longerdirectly connected to the body as a ground return, but remains withinthe device housing 10 with its dropping resistor in FIG. 6 connected tothe skin 11 (ground) to complete the circuit. This ground is essentiallyneutral. The negative polarity is in electrical contact with the skin 11through the aforementioned wetted, long wool intervenor 76, and thenthrough a wetted membrane 74 on the skin which acts as a collector forthe analyte. Of course, for other applications these polarities could bereversed and, again, only a single polarity 2 would be in contact withthe skin.

[0099] The present invention also provides a system to assay or measurethe sample. A pair of electrodes 72 a, 72 b are provided facing eachother with analyte selective enzyme coated on one electrode, e.g., theworking electrode 67, or, alternatively, on the membrane 74 facing theworking electrode. A bi-layer membrane (BLM) is inserted between theseelectrodes 67, 68 and serves the purpose of connecting directly to theskin 11 on one end while the other end is in contact with the longnarrow intervenor 76 that is connected to the high voltage negativesource at 64 (FIG. 4). When wetted with an electrolyte of pH 7.4, acontinuous circuit is provided from this high voltage source to the skin(with felt pad 76 and membrane 74 in between). Thus, in accordance withthe invention, a “sandwiched” bi-layer membrane 74 in between an enzymecoated electrode(s) 67, 68 or membrane 74 is provided as a mechanicalstructure to extract the analyte sample and convey it to any appropriatedigital measurement subsystem 32 (FIG. 5).

[0100] To initially demonstrate the efficacy of the invention and itsoperating principles, a commercially available ExacTech® instrument wasexperimentally modified to be compatible with a prototype noninvasivemeans of analyte sampling of the present invention. This required thatthe ExacTech® test strip containing the enzymes and mediator be slit inhalf lengthwise. The chemically coated strip was then mounted with thetwo chemical surfaces facing each other and an electrically neutralnylon membrane was then inserted between these strips and provided anelectrical and physical connection directly to the skin 11 on one end,with the other end in contact with the long narrow intervenor 76 thatwas connected to a 60 volt D.C. negative source.

[0101] The biosensor 70 circuit 32 is separate from the withdrawalcircuitry 30, 31 in FIG. 5 and comes into play only after the analytesample is withdrawn. The dosimetry circuit turns the device on for thepredetermined setting of 15 ma./sec. to extract the analyte. Uponcompletion of this cycle, the readout in the form of the commerciallyavailable ExacTech® meter was activated and provided a reading on itsdigital display. Thus, we were able to run a series of tests confirmingaccuracy and repeatability of data against blood samples done in theintended manner of normal use for the ExacTech® unit.

[0102] Of course, in the commercial use of the noninvasive means ofsampling of the present invention, there is no intention to use theExacTech® sensing device as a detector. Any number of detection systemsare available, including those in the public domain. The ExacTech® unitis primarily centered on its mediator system using ferrocene derivativesas an oxidant to effect transfer of electrons, and its description hereis solely for the purpose of describing early experiments in thedevelopment of the present invention.

[0103] In accordance with the invention, electronically produced gasesserving as mediator are generated at the high voltage negative terminal.These gases are created by the electrolysis action that takes placesince the electrodes are immersed in a water solvent or electrolyte andconnected to a source of voltage. The negative polarity, besidesproducing the necessary current to withdraw the analyte, also produceshydrogen gas at the negative pole which migrates towards the positivepole and thus passes through the membrane 74 and between the biosensorelectrodes 68, 69. The hydrogen gas is a reduction agent and reductioncannot exist without oxidation. This oxidizes the immobilized enzymes onthe electrodes/membrane and the captured glucose analyte. This alsocauses electron transfer to the electrodes that is proportionate to theconcentration of analyte.

[0104] Hydrogen gas is an excellent redox species and is far superior tothe “one shot” mediator of prior art devices, such as the well-known andcommercially available ExacTech® device, because it comes from arenewable source. This process also produces the halogen chlorine whichaids in oxidation formation.

[0105] In addition, in accordance with the invention, the high voltagesource is dosimetry controlled and, therefore, not only quantitativelycontrols the analyte withdrawal but also controls the quantity of theaforementioned hydrogen/chlorine gas mediator which is generated.

[0106] This negative electrode generated hydrogen also serves otherimportant functions. Since hydrogen has a special affinity for palladiumand will permeate its surface, this may be used to advantage byproviding a sensor electrode of palladium. Hydrogen interacts with thepalladium to lower resistance. If the working electrode 67 is palladiumand the second electrode 68 of the hydrogen resistive alloy NASA-23 orits equivalent, the resistance or work function between both electrodesis lowered. Because the NASA-23 or equivalent counter electrode 58 isimpervious to the hydrogen gas, it serves as an excellent referenceelectrode relative to the palladium electrode 67.

[0107] Still other benefits accrue when hydrogen ions combine with thesolvent water molecules to create hydronium ions. The hydronium ions arecrucial to the cellular processes which lead to enzyme catalysis andmembrane transport.

[0108] In accordance with the invention, very high potentials (over 1v.) are provided to cause the redox reaction. There is a two-stepprocess, i.e., 1) a high voltage to cause the redox (generated by thereducing agent hydrogen), and 2) then revert to an extremely smallvoltage (under 1 v.) to activate the transducer and readout system 32(FIG. 5). This occurs almost instantaneously because the conventionaltime of 20-30 seconds to await the redox reaction has already takenplace in much less time by the high voltage caused hydrogen that led tothat event in much less time than any prior art device.

[0109] Accordingly, and in view of the foregoing, the process of thepresent invention includes application of a large negative voltage to asmall area of the skin 11 to cause the electro-osmotic withdrawal ofbody fluids. This same high voltage has another attribute in that itgenerates hydrogen—the same hydrogen gas that will lead to the oxidationof the glucose enzyme(s) that separates out the glucose analyte frominterferents. This causes the cycle of events that will result inelectron transfer from the closely associated enzyme(s) coatedelectrodes 67, 68 to give a reading of glucose concentration. Moreover,the source for the hydrogen is unlimited and repeatable, thereforemaking the process available on demand without the physical presence ofany consumable chemical mediators. Since the enzymes are reusable, theeconomy and simplicity of operation of such a device provides clearadvantages to the patient.

[0110] To reuse the device 10 and obtain new glucose readings and repeatthe events leading to insulin infusion, the second half of the one cyclelong signal reverses polarity and returns the system to neutral.Alternatively, the patient can wait several minutes for the chemicals ofthe just concluded test to dissipate.

[0111] Another feature of the invention that improves the minutesampling taken through the unbroken skin 11 is the use of theamplification or regeneration capability of certain chemicalcombinations. If the electrodes 67, 68 are coated with coupled enzymes,such as glucose oxidase or glucose dehydrogenase in the presence ofcofactors NAD/NADH and NADPH or NADH, then the extremely minute analytecoming through the skin is “ping ponged” between competitive enzymes andtherefore multiplied. Another benefit of this is improved separationbetween the target glucose and interferents.

[0112] Hence, various aspects of the present invention facilitatenoninvasively withdrawing body fluid and provide novel sensor technologyto create a mediator and to control the quantity of this mediator foraccurately determining analyte concentration for diagnostic purposes.These inventions can be used separately or in combination, and both usecommon components that have multiple functions. This dual capability ofnoninvasive sampling and controlling the target inorganic or organicsubstance is a linchpin to the control and operation of a therapeuticdrug delivery unit such as that described in U.S. Pat. No. 5,224,927 bythe same inventor, Robert Tapper, as the present invention. This “closedloop” arrangement provides for self-regulated insulin infusioncontrolled by the monitored glucose reading using the biosensor 70described above. The entire device can fit into an externally worn,topically applied “patch”, as illustrated in FIG. 1.

[0113] Another important feature referred to in U.S. Pat. No. 5,224,927is the ability of this device to adjust the pH of the drug deliveryreservoirs and/or the biosensor skin contact membrane 74 (known as BLMor s-BLM). The pH adjustment range is 4 to 8 and can aid in permeabilityfor both infusion of drug or increasing withdrawal of analyte. Forinstance, in view of the nonconductive wetted collection bi-layermembrane 74 (BLM) in contact with the skin 11, and in view of the poorlyconductive insulin in the drug delivery chambers 18 a, 18 b, optimalperformance would take place if the solution were adjusted to theappropriate pH. An important function of the s-BLM is that it be used asa pH probe for pH measurement. The resulting pH data is then the basisfor a pH control circuit to adjust pH as needed.

[0114] The aforedescribed system of the present invention relates inparticular, and by way of example, to the needs of a diabetic. Anotherneed of the diabetic is that they be given a “bolus” shot of insulin atmealtime. A bolus shot requires the infusion of a large dose of insulincompared to their baseline maintenance level. The system described inU.S. Pat. No. 5,224,927 is readily adapted to meet this demand for anextra large dose in the following manner.

[0115] By activating the designated electrical bolus switch 52, bothdrug delivery reservoirs 18 a, 18 b of the patch 10 are made activesimultaneously instead of their normal operating mode of sequential drugdelivery (due to the very slow A.C. operating signal). Since the bolusswitch 52 causes both reservoirs 18 a, 18 b to deliver insulinsimultaneously by giving them the identical negative polarity, thedosage is thereby doubled over baseline.

[0116] As previously indicated, the positive polarity stays within thehousing of the electronic patch 10 and is connected to the skin 11through a dropping resistor; see FIG. 6. The skin 11 or ground isrelatively neutral at this point. This feature lifts the positivepolarity off the skin 11, thereby eliminating the more painful andnon-contributing positive polarity from skin contact. This, in turn,allows the patient to at least double the electrical current setting,thereby again doubling dosage, for a total of four times overmaintenance level for short term delivery. For this short term deliverya D.C. signal is used. Because it is a D.C. signal, skin injury could beexpected unless corrective action were taken. Previously, the use of thepH control circuit served the singular purpose of optimizingpermeability and therefore delivery, by making the solvent compatiblewith the drug of choice and its polarity. In accordance with the presentinvention, pH control is also used to prevent skin injury when usingD.C. for the short term. For instance, in the example cited above, thenegative polarity was used to drive insulin from both reservoirs 18 a,18 b. The injurious sodium hydroxide generated at the negative pole mustthen be offset. This can be done by pretreating with the positivepolarity, thereby building an acidic reserve pH of approximately 4 (byway of example) in the drug delivery reservoirs. Drug delivery is thenactivated with a negative polarity driving the pretreatment pH up towardthe alkaline state. Before the reservoirs reach pH 8, the deliverysignal must be stopped for another short dosage of pH 4 caused by thepositive polarity. Thus, injury is prevented by avoiding extremes of pHas measured by the s-BLM probe.

[0117] The invention also includes a unique electrode system that allowscurrent to be elevated at least 200% over present levels. The large drugdelivery electrodes 16 a, 16 b are shown in FIG. 9. Another pair ofancillary electrodes 84 a, 84 b have been added on the outside perimeterof the electrodes 16 a, 16 b that also cross between and are insulatedfrom the electrodes. These outer ancillary electrodes 84 a, 84 b aretypically driven at a frequency of approximately one cycle per minute.This is the second harmonic of the basic drug delivery generator with afrequency approximately one cycle every two minutes. It has beendiscovered that the use of the electrodes 84 a, 84 b to deliver sodiumsalicylate is able to mask the pain sensation of the drug deliveryelectrodes 16 a, 16 b so as to facilitate vastly increasing theelectrical current levels.

[0118] In accordance with the invention, it has been discovered thatsodium salicylate delivery also minimizes skin injury.

[0119] Furthermore, the dual frequency process also is effective inaccommodating the transport times of different size molecules andremoving clutter.

[0120] Another important need for a bolus dose is in the field ofanesthesia since it is desirable for quick action to alleviate pain. Thesame procedure for elevated infusion applies as above with pH control toavoid injury, but may require switching polarities since many analgesicsare positive. In this regard, and referring again to FIG. 9, a D.C.signal is used with novel circuitry to obtain greatly elevated drugdelivery levels without skin injury or pain. To lessen pain and skininjury from the positive reservoirs containing drug delivery electrodes16 a, 16 b, we connect these electrodes through a dropping resistor ofperhaps 5 k to 20 k instead of connecting directly to the positiveterminal of the voltage supply. This causes a large drop across theresistor and makes the electrode relatively less positive than thesource voltage. Electrical current still flows because the negativepolarity is directly connected to the skin 11 through the wetted pad 74.The result is a lifting and isolation of the pain-causing high positivevoltage relative to the skin. This allows increased levels of electricalcurrent and therefore faster therapy. Diminished positive voltage at theskin also decreases the potential for irritation from this contact.Importantly, it has been discovered that adding sodium salicylate to thenegative pad also diminishes skin injury which would normally be aconcern with a D.C. device.

[0121] The aforedescribed artificial pancreas of the present inventionhas obvious advantages over present day invasive systems that includeexpensive and risky implants.

[0122] It is to be understood that the noninvasive biosensor describedabove used glucose as the target analyte only as an example and not byway of limitation. For instance, there are over 250 differentdehydrogenases and several thousand enzymes. Besides glucose analysis,important diagnostic applications could include urea, creatinine,lactate, cholesterol, aspirin and paracetamol among others. Also,noninvasive sample analysis may be made of body fluids to compare tonormal levels or to track administered drug levels.

[0123] Since the present invention focuses on a means of determining theconcentration of chemical or body fluid components to assess acondition, another important application is suggested. Duringiontophoretic drug delivery, it has long been an enigma as to what partof the reservoir drug has been infused. In this regard, the same meansof determining concentration with the biosensor 70 described above maybe applied to assessing the drug remnant in a drug infusing device,therefore assuring the user of adequate drug availability, etc. Thisoccurs because a decrease of concentration indicates percutaneousabsorption into the body of the solute or drug. This information mayalso be important to the investigator during the testing of a new drug,for quantitative analysis of drug related to an effect. The presentinvention thus nominally replicates the extremely expensive HPLC labinstrument at a fraction of the cost.

[0124] Still another important application, in accordance with theinvention, comes about as a result of this ability to assess drugconcentration in an iontophoretic drug delivery reservoir. It has alwaysbeen a problem to have an adequate supply of drug available in the drugreservoir for long term, continuous delivery. It is not practical tomake an overly large patch because it must be worn and would meetpatient objection. Also, the literature places concentrationrestrictions on iontophoretic drug delivery to 2% solutions, claimingreduced flow above this point because of ionic clutter. In accordancewith the present invention, a novel way of eliminating this problem andallowing delivery over time with a relatively small patch is to providea reserve reservoir that contains a concentrate of the desired drug inaqueous solution. The concentrate is considerably over 2%—perhaps 20 or50%. Upon receiving information from the drug delivery reservoir thatthe concentration is less than the initial filling of 2%, the biosensor70 triggers the reserve reservoir to release enough of the concentrateto make up the difference that was infused. In this manner, the drugreservoir is continuously replenished.

[0125] The structure of the reserve reservoir (not shown) is a separatecompartment for the concentrate with a membrane covered opening. Themembrane has a voltage across it with selective polarities to act as avalve to open or shut off the flow of concentrate as needed. This actionmay be enhanced with an ion exchange membrane. The solvent isreplenished automatically by virtue of the fact that an A.C. signal isused. This causes the hydrogen and hydroxide ions to migrate together toform water.

[0126] Various other embellishments known in the art can be practiced inaccordance with this invention. They include immobilization of theenzyme biocomponent and restriction of the flow of analyte diffusion.The best biosensor design is to build a “direct” device withbiocomponents immobilized directly on the transducer. Othercharacteristics of construction include the close proximity of thebiological and physicochemical components to each other to improveefficiency.

[0127] The present invention also provides in combination with theaforedescribed sample withdrawal and assay, and in response toelectrical input from the assay subsystem, a new and improved method andapparatus for applying electrical energy topically to a suitable surfaceof a biological subject, such as the skin of a human body, particularlyfor the long term administration of medicaments and the like or forother electrotherapeutic treatment, and by which the aforementioneddeficiencies and undesired side effects are greatly minimized and may beeliminated. Moreover, the system of the present invention is relativelyinexpensive to manufacture, can be physically packaged in a completelyself-contained, relatively simple and compact configuration, troublefree and reliable in use, is capable of higher drug administration ratesand drug concentrations, can deliver multiple drugs simultaneously in asimple manner, can control pH at the delivery site, is capable ofdelivering large and/or heavy molecule drugs, is a more effectivebactericidal, and is arranged to be safely, simply and reliably operatedfor self-treatment by an average person in normal home use, even forextended periods of several days at a time. Furthermore, it iscontemplated in the practice of the invention that electrical impedanceat the administration site on the patient can be substantially reducedto vastly improve permeability and penetration and thereby furtherenhance medicament delivery.

[0128] In this regard, the present invention is directed to a new andimproved system for analyte sample withdrawal and subsequentiontophoretic drug administration, in response to an assay measurementsignal, which includes conducting direct electrical current through theskin of a body, and periodically reversing the electrical current andconducting the electrical current through the skin in the oppositedirection, to effectively deliver very low frequency A.C. current,substantially in the critical range of approximately 0.0027 Hz to 10 Hz.It has been discovered (see U.S. Pat. No. 5,224,927) that, within thissubstantially critical frequency window between approximately sixminutes per full cycle and approximately ten cycles per second, adramatic cancellation of skin damaging ions takes place. At frequencieshigher than approximately 10 Hz, no substantial effective delivery takesplace. At frequencies lower than approximately 0.0027 Hz, the risk ofskin injury increases substantially.

[0129] As previously indicated, it is well known that the positiveiontophoretic electrode, in addition to its primary function of drivinglike polarity ionic substances into the skin of a subject, unfortunatelyproduces skin damaging hydrochloric acid as well. Likewise, the negativeiontophoretic electrode, in addition to its primary function of drivinglike polarity ionic substances into the skin, unfortunately alsoproduces skin damaging sodium hydroxide. However, within the aforestatedfrequency range of the present invention, either driving polaritydelivers the desired ionic therapeutic substances, but also cancels theundesired skin damaging ions with the reverse portion of the electricalcycle. The reason for neutralization of the harsh injury producingchemicals, i.e., hydrochloric acid and sodium hydroxide, is that both ofthese chemicals require a finite period of time on the skin to causedamage. Hence, these damaging chemicals are made to cancel each otherbefore damage takes place, by critical frequency selection of the A.C.driving signal. Therefore, optimization of a long sought therapeuticdevice with reduced side effects has been achieved.

[0130] In this regard, electronic circuitry is provided to automaticallyimpose the reversal of electrical current at regularly repeatingintervals of time, in accordance with the aforedescribed substantiallycritical frequency range, and the system can be adjusted to conduct theiontophoretic treatment at any desired level of electrical current.

[0131] As previously indicated, the present invention provides a methodand apparatus for electrical dosimetry control for the electro-osmoticwithdrawal of fluids from a biological subject to obtain an analytesample dosage being determined by the product of time and electricalcurrent, wherein electrical current magnitude and time are fixed toautomatically assure consistent sample withdrawal from one procedure toanother and thereby maintain calibration for accuracy.

[0132] In accordance with the invention, the same dosimetry controlsubsystem can be switched to control the dosimetry of the slow A.C.signal driven iontophoretic administration subsystem, independently ofwhether or not the sample withdrawal and biosensor assay subsystems arealso employed.

[0133] Hence, the present invention includes, in an electro-osmoticwithdrawal system, a subsystem for electrical dosimetry measurement andcontrol, wherein the product of administered electrical current and timefor total dosage is maintained constant, while either variable, time orelectrical current magnitude, may be changing. A system which can beadapted for implementing such measurement and control is described inU.S. Pat. No. 4,822,334 issued Apr. 18, 1989, inventor Robert Tapper(the same inventor as the present invention) and all of the disclosureof this patent is specifically incorporated by reference in thisspecification as if set out completely herein. The disclosure of thispatent is directed to an iontophoresis environment, but, in accordancewith the present invention, the control system is adapted forelectro-osmotic sample withdrawal rather than iontophoretic fluiddelivery.

[0134] Such a system, by way of example and not necessarily by way oflimitation, includes means for applying electrical current to a load,such as a human patient, over time, together with means forautomatically varying the magnitude of the current and/or time to ensureconsistent sample size withdrawal. The system includes means forestablishing the magnitude of the desired total withdrawn sample sizedosage in terms of delivered time-current product and means for sensingthe magnitude of the electrical current and converting that magnitude toa voltage for varying the frequency of a voltage controlled oscillatoras a function of the electrical current magnitude. Means are alsoprovided for measuring and accumulating the electrical output of theoscillator over time, in a suitable counting device, as an indication ofthe actually delivered time-current product. In addition, means areprovided for comparing the delivered time-current product registered inthe counter, as a running measure of electro-osmotic sample withdrawalduring the administration procedure, with the desired total dosagepreviously established, so that the application of electrical currentwill be automatically terminated when the time-current product actuallyadministered equals the desired total dosage, i.e., the size of thesample for subsequent assay.

[0135] In this way, desired sample withdrawal dosage is consistently andreliably delivered with great precision even though the electricalcurrent may be varied during the sample withdrawal.

[0136] Referring now to FIG. 5 of the drawings, there is shown in detaila system for sample withdrawal and dosimetry control including a powersupply, A.C. generator and control circuitry subsystem 30 and adosimetry circuitry subsystem 31, as well as an output sensor andreadout subsystem 32, shown by way of example as suitable for glucosemeasurement.

[0137] The electro-osmosis electrical current is sensed and converted toan appropriate voltage which is directed to a suitable voltagecontrolled oscillator (VCO) 34. In FIG. 5 the oscillator 34 generatesoutput pulses whose frequency is proportional to the magnitude of theload current, and this electrical pulse output is directed to a counter35 which essentially integrates the applied load current over time, viathe counting of oscillator output pulses, to obtain an electricalcurrent-time product providing a running measure of dosage actuallywithdrawn as a sample from the biological subject.

[0138] The state of the counter 35, i.e., the actually withdrawn sampledosage, is directed to a digital comparator where it is compared withthe selected total dosage desired and, when the running measure ofdosage indicated by the counter matches the total dosage selected, thesample withdrawal process is terminated by an appropriate output fromthe digital comparator. In this way, any variations in current and/ortime during the sample withdrawal procedure will still provide aconsistently reliable total dosage from one procedure to the next and,therefore, the parameters of time and electrical current can vary fromsubject to subject and from time to time with the same subject, withoutinterfering with the precise total sample dosage withdrawn from thepatient over the course of the procedure.

[0139] The sample withdrawal current is converted to a voltage whichestablishes the frequency of oscillation of the oscillator 34. Thecounter 35 accumulates the electrical output of the oscillator 34 overtime, as an indication of the actually delivered time-electrical currentproduct representing a running measure of dosage during the samplewithdrawal procedure.

[0140] The electrical state of the counter 35 is then directed as inputto the digital comparator 36 and, when the state of the counter 35equals the desired total dosage to be withdrawn, represented by apredetermined dose already set in the digital comparator, an electricaloutput is generated from the comparator. This output is directed, overline 32, to the subsystem 38 to terminate the sample withdrawalprocedure once the desired total dosage has been electro-osmoticallywithdrawn from the patient. Consequently, the desired total dosage isconsistently and reliably withdrawn from the patient, with greatprecision, from one administration procedure to the next. This preciserepeatability occurs even though the electrical current or time may varysubstantially during the withdrawal procedure.

[0141] The subsystem 30 also includes an oscillator and wave shapingunit 40 directing output over line 42 to a unit 43 for voltage tocurrent conversion and output current reversal, which is under thecontrol of input from an output voltage generator (switching regulator)unit 44 and the output shutdown latch and ramping unit 38 via an outputcurrent detection unit 39. The unit 43, in turn, directs samplewithdrawal current output to the patient (load) at a pair of output pins61, 62 which are also used to control subsequent iontophoretic deliveryin response to sample assay.

[0142] The unit 43 also provides output to the VCO 34 in the dosimetrysubsystem 31 and to a suitable failsafe circuit which, in turn, has anoutput directed shutdown unit 38.

[0143] An electrical output switching and control unit 47 provides a(neutral) ground return for the sensor 70 at pin 63, the 60 voltnegative output to withdraw a sample of analyte at pin 64, a groundreturn for pH control at pin 65, and a ground return for bolus deliverytreatment at pin 66.

[0144] The control unit 47 also provides an output (labeled 61, 62, 63,64, 66 in FIG. 5) to the target for pH control, as well as an output(labeled 61, 62 in FIG. 5) providing high electrical current for bolustreatment (which also serves as a reservoir for general drug delivery).

[0145] The pins 67, 68 are connected to the sensor output for the meterand associated circuitry of subsystem 32.

[0146] A VCO accuracy feedback unit 49 also receives the output from theVCO 34 which has been provided to the counter 35 and the unit 49provides control input over line 50 to the VCO.

[0147] The digital comparator unit 36 provides input over line 37 to theunit 38 which, as previously indicated, provides input to the unit 43.

[0148] A low battery sensing unit 52 also provides input to the shutdownunit 38.

[0149] The aforementioned pin numbers 61, 62, 63, 64, 65, 66, 67 and 68correspond to the labeling of electrical connections for the samplewithdrawal, biosensor, assay and iontophoretic administration patch 10shown in FIGS. 2-4 of the drawings.

[0150] It will be apparent that the various electrical subsystemsindicated in FIG. 5 of the drawings can be implemented readily by thoseof ordinary skill in the art without the exercise of inventive skill. Inthis regard, Appendices A and B, attached to the specification andspecifically incorporated herein, illustrated, by way of example,presently preferred embodiments of electrical circuitry suitable forimplementing the primary subsystem schematically depicted in blockdiagram format in FIG. 5 of the drawings, for practice of the invention.

[0151] Hence, the present invention satisfies a long existing need inthe art for painless, accurate, non-invasive analyte withdrawal andanalysis and subsequent controlled delivery of therapeutic agents inresponse to such analysis. The present invention clearly fulfills theseneeds.

[0152] It will be apparent from the foregoing that, while particularforms of the invention have been illustrated and described, variousmodifications can be made without departing from the spirit and scope ofthe invention. Accordingly, it is not intended that the invention belimited, except as by the appended claims.

I claim:
 1. In the electronic dosimetry control system for iontophoreticdelivery of therapeutic agents to a biological subject, the combinationcomprising: means for delivering a slow A.C. electrical current to theskin of a biological subject to transport a therapeutic agent to thesubject; means for varying the time period over which said electricalcurrent is supplied to the biological subject in accordance with thedesired dosage to be delivered to the biological subject; and means forterminating said electrical current delivered to the biological subjectwhen said electrical current-time product equals the desired totaldosage.
 2. An electronic process for controlling iontophoretic deliveryof therapeutic agents by electrical current applied over time to abiological subject, comprising the steps of: establishing a total dosageto be delivered, in the form of a slow A.C. electrical current-timeproduct, to the biological subject; and automatically varying the timeperiod over which said electrical current is applied by accumulating theelectrical current-time product until termination at the selecteddosage.
 3. In an electronic control system for iontophoretic treatmentof a biological subject, the combination comprising: means for applyinga slow A.C. electrical current to a biological subject over time; meansfor establishing the magnitude of the desired total treatment dosage tobe applied to the biological subject, in terms of electricalcurrent-time product; means for sensing the magnitude of said electricalcurrent and for converting said magnitude to an electrical signal; meansfor measuring said electrical signal over time as an indication of theactual electrical current-time product; means for comparing said actualelectrical current-time product with said desired total sample volume tobe withdrawn; and means for terminating said electrical current whensaid electrical current-time product equals said desired total treatmentdosage as established by said determining means.
 4. In an electroniccontrol system for iontophoretic treatment of a biological subject, thecombination comprising: means for conveying a slow A.C. electricalcurrent to the skin of a biological subject; means for determining themagnitude of said electrical current; means for controlling the timeperiod over which said electrical current is supplied to the biologicalsubject; control means for automatically determining the therapeuticdosage to be applied to the biological subject; means for electricallymeasuring the actual dosage applied to the biological subject as afunction of said electrical current and time; and means for terminatingsaid electrical current applied to the biological subject when saidelectrical current-time product equals the desired total dosage asestablished by said control means.
 5. In an electronic control systemfor iontophoretic delivery of a therapeutic agent to a biologicalsubject, the combination comprising: means for delivering an electricalcurrent to the skin of a biological subject; means for varying the timeperiod over which said electrical current is supplied to the biologicalsubject in accordance with the desired dosage to be delivered to thebiological subject; means for terminating said electrical currentapplied to the biological subject when said electrical current-timeproduct equals the desired total dosage; and means for intermittentlyreversing said electrical current, at a relatively low frequency whichprevents skin damage, between approximately 20 times per second andapproximately once every three minutes.
 6. An electronic process forcontrolling iontophoretic delivery of a therapeutic agent by a slow A.C.electrical current applied over time to a biological subject, comprisingthe steps of: selecting a total dosage to be delivered, in the form ofan electrical current-time product, from the biological subject;automatically varying the time period over which said electrical currentis applied by accumulating the electrical current-time product untiltermination at the selected dosage; conducting said electrical currentthrough a surface of said subject in a first direction from a firstelectrode to a second electrode on said subject; and intermittentlyreversing, at a relatively low frequency which prevents skin damage,between approximately 20 times per second and approximately once everythree minutes, the polarity of said electrodes to cause said electricalcurrent to flow in a second direction opposite to said first direction,whereby iontophoretic delivery is accomplished at the desired dosage. 7.A process as recited in claim 6, including the additional step ofelectrically connecting both of said electrodes in parallel for bolusdelivery.
 8. A process as recited in either of claims 6 or 7 whereinoperation is conducted at plural frequencies.
 9. In a patch adapted tobe worn by a biological subject, the combination comprising; meanswithin said patch for electro-osmotic withdrawal of fluid sample;biosensor means within said patch for evaluation of said samples; andmeans within said patch for providing iontophoretic treatment to abiological subject in response to said biosensor means.
 10. In a patchadapted to be worn by a biological subject, the combination comprising:means within said patch for providing iontophoretic treatment to thebiological subject; and dosimetry control means within said patch forcontrolling the dosage of said iontophoretic treatment as a function ofthe product of time and electrical current applied to the subject.
 11. Acombination as recited in claim 10 wherein said electrical current isgenerated by a slow A.C. signal.